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Virus Specific Immune Lymphocytes (Virus-CTL) in the Treatment of Opportunistic Viral Diseases Post Transplantation

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ClinicalTrials.gov Identifier: NCT03159364
Recruitment Status : Recruiting
First Posted : May 18, 2017
Last Update Posted : February 16, 2018
Sponsor:
Information provided by (Responsible Party):
Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute

Brief Summary:
Epstein Barr Virus (EBV) and Cytomegalovirus (CMV) result in significant morbidity and mortality in hematopoietic stem cell transplantation (HSCT) patients in China. Antiviral drugs are usually used for prophylactic purposes and treatment after early detectable viral load. Unfortunately, some patients may develop resistance to antivirals. In addition to patient with HSCT, immune compromised patients may also been the targets for these opportunistic viruses. Thus in this study, the safety and efficacy of CMV and EBV specific cytotoxic T cells (CTLs) will be determined.

Condition or disease Intervention/treatment Phase
Virus Infection EBV Infection Cytomegalovirus Infections Adenovirus Infection BK Virus Infection Biological: CMV/EBV/ADV/BKV specific CTLs Phase 1 Phase 2

Detailed Description:

Background:

Opportunistic infection virus related diseases are major causes of transplant-related morbidity and mortality in immunosuppressed patients, especially in the early post-transplant period. CMV, EBV, adenovirus (ADV), BK virus (BKV) and other viruses after transplantation, which may lead to life-threatening infections.

Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) reactive with specific viral antigens has proven to be effective without stimulating acute graft-versus-host disease (GVHD) owing to the significantly reduced nonspecific alloreactivity. Here, the investigators aim to evaluate the safety and efficacy of multiple infusions of mix opportunistic infection virus peptide cytotoxic T lymphocytes cells in patients.

Objective:

Primary study objectives: Infusion of autologous or allogenic Virus-CTL to patients by I.V., to evaluate the safety.

Secondary study objectives: To evaluate the antiviral efficacy of IV-infused autologous or allogenic Virus-CTL cells.

Design:

Peripheral blood mononuclear cells (PBMC) will be obtained through apheresis. T cells from PBMC will be activated and enriched by dendritic cells with virus specific peptides. Cell preparation time is approximately 12-17 days. Subject will receive infusions of 1x105~4x106 cells/kg body weight of virus-CTL via IV infusion at 4 times. Patients are followed 1 week after the final infusion, monthly for 3 months, and then every 3 months until the trial ends.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II and Multicenter Trial of Virus Specific Immune Lymphocytes (Virus-CTL) in the Treatment of Opportunistic Viral Diseases Post Transplantation
Actual Study Start Date : July 15, 2017
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Infusion of CMV/EBV/ADV/BKV specific CTLs
Repetitive CTLs infusion to treat CMV/EBV/ADV/BKV activation and infection
Biological: CMV/EBV/ADV/BKV specific CTLs
Patients will receive approximately 1x10^5~4x10^6 CTLs/kg as a single infusion via IV injection and may receive 1 to 4 additional infusions at intervals of one week.




Primary Outcome Measures :
  1. Using CTCAE 4 standard to evaluate the level of adverse events after receiving autologous or allogenic virus-CTL infusion [ Time Frame: 24 weeks ]
    to evaluate the level of adverse events with CTCAE 4

  2. viral load change after CTL infusion [ Time Frame: 3 months ]
    The viral load response to the CTL infusion will be assessed by CMV/EBV specific PCR of peripheral blood everyday after infusion.


Secondary Outcome Measures :
  1. The incidence of Ⅱ~Ⅳ°aGVHD within 30 days after the last dose of CTL infusion [ Time Frame: 1 months ]
  2. Reconstitution of antiviral immunity monitored by flow cytometry [ Time Frame: 6 months ]
  3. Number of patients with chronic GVHD [ Time Frame: 6 months ]


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Ages Eligible for Study:   6 Months to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects with or without hematopoietic stem cell transplantation / organ transplant recipients need to meet the following conditions:

  • Evidence of cytomegalovirus (CMV), EBV virus activation (viral DNA, immunohistochemical cytology positive) after transplantation; contraindications or invalid to antiviral drugs.
  • subjects with virus DNA increased in the 2 consecutive peripheral blood samples (≥ 1000 genomic copies / ml peripheral blood) at least 24 hours apart.
  • initial hematopoietic reconstitution: neutrophils (ANC) ≥ 0.5x109 / L, platelet (PLT) ≥ 20x109 / L.
  • Patients with viral disease (organ / tissue virus infiltration) symptoms, fever, diarrhea, or lymphadenopathy, regardless of the level of peripheral blood Virus DNA, and confirmed by the presence of viral DNA or virus antigens within body fluid or biopsy.
  • The subject / guardian has signed a written consent form before any trial begins.

Proper renal and hepatic functions (ULN denotes "upper limit of normal range"):

  • Creatinine ≤ 2*ULN.
  • Bilirubin ≤ 2*ULN.
  • SGOT ≤ 3*ULN.
  • SGPT≤ 3*ULN.

If Virus-CTL is not from the patient's own, then the provider of Virus-CTL needs to meet the following criteria:

  • did not receive chemotherapy or radiotherapy within 4 weeks prior to blood collection, and did not take any steroids for the previous week, did not use Penicillin or β-lactam antibiotics, or the lowest dose of other antibiotics.
  • white blood cells ≥ 3,500 / μl, lymphocytes ≥ 750 / μl.
  • Obtain a signed informed consent from the patient and / or the guardian or the donor of the BMT recipient.
  • human immunodeficiency virus (HIV) test was negative.
  • physical examination in line with the standard of healthy blood donors.

Exclusion Criteria:

  • Subject or the donor of BMT recipient infected with HCV (HCV antibody positive), HBV (HBsAg positive), HIV (HIV antibody positive), HTLV (HTLV antibody positive), Treponema pallidum antibody positive or TB culture positive.
  • GVHD (graft-versus-host disease) performance score = II-IV.
  • Subject is albumin-intolerant.
  • Subject with life expectancy less than 8 weeks.
  • Subject participated in other investigational somatic cell therapies within past 30 days.
  • Subject with positive pregnancy test result.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03159364


Contacts
Contact: Lung-Ji Chang, PhD 86-13671121909 c@szgimi.org

Locations
China, Guangdong
Shenzhen Geno-immune Medical Institute Recruiting
Shenzhen, Guangdong, China, 518000
Contact: Lung-Ji Chang, PhD    86-13671121909    c@szgimi.org   
Sponsors and Collaborators
Shenzhen Geno-Immune Medical Institute
Investigators
Principal Investigator: Lung-Ji Chang, PhD Shenzhen Geno-Immune Medical Institute

Responsible Party: Lung-Ji Chang, President, Shenzhen Geno-Immune Medical Institute
ClinicalTrials.gov Identifier: NCT03159364     History of Changes
Other Study ID Numbers: GIMI-IRB-17009
First Posted: May 18, 2017    Key Record Dates
Last Update Posted: February 16, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute:
Virus-CTL
EBV
CMV
ADV
BKV

Additional relevant MeSH terms:
Infection
Communicable Diseases
Virus Diseases
Cytomegalovirus Infections
Adenoviridae Infections
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Tumor Virus Infections